Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial

Abstract

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 g/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year eventfree survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence.

Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP–RTSG 2016 protocol

“…Since the first SIOP protocol started in 1971, treatment intensity has been successfully reduced for the majority of patients with Wilms tumours, and survival has risen to 90% 2,[6][7][8][9][10] . Consequently, the identification of additional predictive and prognostic factors is increasingly important to improve the stratification of patients according to their individual risk.…”

“…Similar to the SIOP−2001 protocol, the UMBRELLA protocol continues to recommend preoperative actinomycin D and vincristine for patients newly diagnosed with Wilms tumour aged ≥6 months, based on results of previous SIOP trials that showed tumour downstaging using this regimen 2,6,8,9,14,17 . This benefit was also independently observed in the randomized, controlled UKW3 trial conducted by the UK Children's Cancer and Leukaemia Group (UKCCLG, previously known as the UK Children's Cancer Study Group) 18 .…”

“…This regimen consists of 27 weeks of vincristine and actinomycin D without doxorubicin. This schedule resulted in a nonsignificant small decrease in event-free survival (EFS) and had no effect on overall survival compared with 27 weeks of vincristine and actinomycin D plus five doses of doxorubicin at 50 mg/m 2 (the standard arm) in the SIOP-2001 trial 2 .…”

Management of Bilateral Wilms Tumours

“…Its use could come at the cost of reduced renal function, particularly in young patients with the added toxicity of anthracycline chemotherapy (42). Fortunately, it has been shown that anthracyclines can be omitted in Intermediate risk stage III cases in SIOP; however, this needs to be determined in stage V cases (43). Other than cardiomyopathy and second malignant neoplasms, renal failure is the most common source of morbidity in BWT.…”

Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors

“…For both groups, tumor histology and stage dictate the intensity of postoperative treatment, with chemotherapy and sometimes radiotherapy. Regardless of the protocol used, overall survival approaches 90% [3].…”